Like statins, cholesterol absorption inhibitors are linked with a lower risk of developing liver cancer.
Photo by Towfiqu Barbhuiya on Unsplash
Past studies have suggested that taking cholesterol-lowering statin drugs may lower the risk of developing liver cancer. In a new study of non-statin cholesterol-lowering medications, one type was linked to lower risks of liver cancer. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.
Cholesterol absorption inhibitors, bile acid sequestrants, fibrates, niacin, and omega-3 fatty acids are types of non-statin cholesterol-lowering medications prescribed to manage cholesterol and lipid levels. The different classes of drugs work in different ways. A team led by Katherine A. McGlynn, PhD, MPH, of the National Cancer Institute, looked for associations between these five types of non-statin cholesterol-lowering medications and risk of liver cancer, the sixth most commonly occurring cancer globally and the third leading cause of cancer mortality.
The investigators used information from the Clinical Practice Research Datalink (CPRD), a primary care database that covers approximately 7% of the United Kingdom population. Their analysis included 3719 liver cancer cases and 14 876 matched controls without cancer. Additional matches were also made based on individuals’ type 2 diabetes and chronic liver disease status.
Use of cholesterol absorption inhibitors was associated with 31% lower odds of liver cancer risk in the overall analysis. These medications were also linked with a lower risk of liver cancer in analyses based on diabetes and liver disease status. The study also confirmed that statins were associated with 35% lower odds of liver cancer.
No associations with liver cancer risk were observed for fibrates, omega-3 fatty acids, or niacin. While bile acid sequestrant use was associated with higher odds of liver cancer risk in the overall analysis, the results of analyses based on diabetes and liver disease status were inconsistent, suggesting that replication of these observations is important.
“As few studies have examined the effects of non-statin cholesterol-lowering drugs on liver cancer risk, the results of our study require replication in other populations. If our findings are confirmed in other studies, however, our results may inform liver cancer prevention research,” said Dr. McGlynn.
One of the biggest stories in HIV in the last year was that a class of medicines called statins could help reduce cardiovascular disease in people living with the virus. In response, treatment guidelines in the United States were quickly updated, but the picture is more complicated in South Africa. Spotlight’s Elri Voigt explores why the case for widespread use of statins by people living with HIV is less compelling in South Africa than in some other countries.
People living with HIV, provided they are stable on antiretroviral therapy, are affected by the same diseases as those who don’t have HIV, including cardiovascular disease, says Professor Mpiko Ntsekhe, head of Cardiology at Groote Schuur Hospital in Cape Town.
The key difference, he says, is that although both groups of people get the same spectrum of diseases, people living with HIV get those diseases more frequently and earlier. One way to think about this, he explains, is to imagine twins who are identical in every way except one is living with HIV. The twin living with HIV is more likely to get cardiovascular disease than the other twin.
And these differences can be substantial. Current evidence shows that people living with HIV have a twofold increased risk of developing cardiovascular disease compared to people not living with HIV, says Professor Hans Strijdom. He is the Head of the Division of Medical Physiology and Deputy Director of the Centre for Cardio-Metabolic Research in Africa (CARMA) at Stellenbosch University. The cardiovascular risk attributable to HIV, Strijdom adds, is now believed to be equivalent to that posed by traditional risk factors such as smoking. This prompted an editorial in 2018 in one of the top cardiovascular journals, Circulation, advocating for HIV to be recognised as a major cardiovascular risk factor.
He explains that people living with HIV who are stable on treatment are living longer, making them susceptible to the normal risk posed by older age. They also have “modifiable risk factors, in other words lifestyle risk factors”, like a higher smoking and alcohol use incidence, as well as increasing rates of being overweight and obesity. Strijdom says that living with HIV, even when someone is stable on treatment, causes low-grade inflammation, which over time increases a person’s risk for cardiovascular disease. “That all in combination are the current theories [of] why we think that they have a bigger risk of cardiovascular disease,” he says.
Important study findings
Arguably, the biggest news from last year’s International AIDS Society (IAS) Conference in Australia was findings from a study on heart disease in people living with HIV. The trial, called REPRIEVE, showed that a class of cholesterol-busting drugs called statins can prevent a lot of cardiovascular disease events in people living with HIV whose cardiovascular disease (CVD) risk score meets a certain threshold. Spotlight previously reported on these findings, which showed that compared to placebo, daily treatment with 4mg oral pitavastatin – a specific statin – led to a 35% reduction in major adverse cardiovascular events (MACE) in people living with HIV classified to be at risk of cardiovascular disease.
When the findings were presented at the IAS conference, the study’s principal investigator, Dr Steven Grinspoon, said that while the researchers still have to assess more of the data collected to get a clearer picture of things, like the mechanisms driving cardiovascular disease across regions and conduct additional sub-group analyses, the study has already shown that using pitavastatin can save lives.
These sub-group analyses were discussed in greater detail at the Conference on Retroviruses and Opportunistic Infections (CROI) held in Denver in March this year. For the most part, the use of pitavastatin in the manner prescribed by REPRIEVE was considered a huge success, and the United States has since changed its guidelines to include the use of statins in the primary prevention of atherosclerotic cardiovascular disease.
Why it is different in South Africa
However, for low-and-middle-income countries like South Africa, the case for pitavastatin might not be as clear-cut. In fact, a panel discussion at CROI was dedicated to exploring the implications of the REPRIEVE findings for such countries.
Ntsekhe, who was a speaker on the CROI panel, tells Spotlight that data from REPRIEVE’s sub-group analyses reveal there was a striking difference in event rates – which in the case of the study are MACE in those who were getting the placebo – by country income status. He explains that as predicted in high-income countries, the event rates were high, while in low-and-middle income countries – particularly in Sub-Saharan Africa – event rates were very low.
He says one of the reasons for the difference in event rates was that the screening tool used in REPRIEVE worked well to identify those people living with HIV who might benefit from pitavastatin in high-income countries like the United States, but it did not work well in Sub-Saharan Africa.
This means using pitavastatin as part of a primary prevention strategy is a much more effective intervention in high-income countries than in low-and-middle income countries like in Sub-Saharan Africa because the cardiovascular disease profile is so different.
Ntsekhe explains the term cardiovascular disease itself is broad and all-encompassing and there are many forms, including valve disease, heart muscle disease, and vascular disease. The dominant form of cardiovascular disease in the high-income countries (which he refers to as the Global North) is known as atherosclerotic cardiovascular disease, which is characterised by a build-up of fatty deposits and plaque in the arteries.
In Sub-Saharan Africa though, Ntsekhe says “atherosclerotic cardiovascular disease is but one of many forms of cardiovascular disease”, taking the fourth or fifth place in the ranking of types of major heart disease.
Research conducted in high-income countries don’t always take differences in disease burden into account, according to Ntsekhe. This means that interventions researched in high-income countries and shown to be effective in that context won’t necessarily work as well in low-and-middle income countries like South Africa.
Strijdom concurs that while results from REPRIEVE in the global context were a game-changer, the findings are not easily transferable to South Africa’s context because pitavastatin is mainly aimed at reducing “bad cholesterol” and coronary artery disease (also called atherosclerosis).
‘Taking money away’
During the panel discussion at CROI, Ntsekhe asked whether Sub-Saharan Africa could justify taking money away from other health programmes that work in order to invest in pitavastatin.
“I said basically what should be a priority for us is a) finding tools that can better identify those at risk and b) continuing to focus on what our local data suggests are the priority areas,” Ntsekhe says.
“If your entire prevention strategy is aimed at atherosclerotic cardiovascular disease, but it isn’t the dominant cause of disease [in your country], you’re going to be treating a whole host of people to try and tackle this thing that affects very few in a sense,” he says.
“It was not anything about REPRIEVE, it was a wonderful study, the hypothesis was tested, and it was shown to be correct, the intervention we know works,” Ntsekhe says. “It really then comes down to regional areas to think very carefully about how best they’re going to get their biggest bang for their buck,” he says. “We have to carefully consider the local context, local burden, we have set local health priorities, and weigh benefit and cost before we adopt new interventions or recommendations.”
SA’s cardiovascular disease burden
While Strijdom says we don’t have great data, he points to a large systematic review and meta-analysis published in 2018 in Circulation, which estimates that around 15% of the total cardiovascular disease burden in South Africa is attributable to HIV. “It’s probably higher than that. I would say that probably about one in five people with heart disease have heart disease because of HIV in South Africa,” he says, adding “that figure is probably only going to increase”.
Because of this, he says, there is a need for proper and clear primary healthcare guidelines specifically aimed at managing cardiovascular disease in people living with HIV, which we don’t currently have.
Strijdom says what we have at the moment since the rollout of the 2019 National ART Clinical Guidelines is very basic guidelines. This involves screening someone who has just been diagnosed with HIV by taking their blood pressure, and testing urine for glucose and proteins, and an assessment of their general cardiovascular disease risk by taking their medical and family history. These guidelines, according to Strijdom, only make provision for routine screening at baseline, but screening guidelines at follow-up visits are insufficient.
“I am, however, aware of the fact that there is progress especially from the integrated chronic disease management model which is currently being piloted in South Africa – and hopefully with that will come much more definitive and universal guidelines,” he says. “The bottom line is that South Africa, in its public health [sector] especially, really very quickly needs to come up with very clear and more comprehensive guidelines to actively manage cardiovascular disease risk in people with HIV.”
Need for annual screening
Strijdom suggest that to improve screening for cardiovascular disease risk in people living with HIV, there needs to be annual screening of people’s weight, their measure of body fat based on height and weight, waist circumference, blood pressure, cholesterol and triglyceride levels as well as testing urine samples for kidney function. There also needs to be a thorough family and medical history conducted for each patient.
“It’s not really a very expensive or very exhaustive list of stuff that you have to do. Unless of course they have specific symptoms and signs that leads you in a specific direction that you then have to perhaps do an ECG [a test used to evaluate the functioning of the heart] or cardiac imaging but that is usually determined by what you get from their history and clinical examination,” he says.
Ntsekhe says public health strategies to combat the growing burden of non-communicable diseases (NCDs), including cardiovascular disease, in South Africa must be strengthened. These include screening and prevention tools like checking a patient’s blood pressure and blood glucose, advising against smoking and alcohol as well as promoting health lifestyle choices like exercise and weight loss. These interventions should be offered to everyone, regardless of whether they are living with HIV or not, he says.
“The thing about NCDs and cardiovascular disease, for the most part, they are diseases of lifestyle and behaviour. So, when you talk prevention, it’s not always about drug prevention,” he says. “It’s more about intensification of those [interventions] that are already in the public domain, are very effective, and cost very little. Many of the public health and primary healthcare guidelines do advise local ministries, local health authorities on what should be happening.”
In terms of public education, Stritjdom says people need to be aware that there is something like high blood pressure. “If people are aware they will come to the clinic and will say please measure my blood pressure,” he says.
“Our health system is understandably focused on infectious diseases, but if we are not careful, we will then be totally unprepared to tackle the epidemic that will have replaced it. Namely, cancer, heart disease, stroke, obesity, diabetes, and it will totally overwhelm our public healthcare system,” he says.
Lung cancer metastasis. Credit: National Cancer Institute
A new study led by investigators from Mass General Cancer Center, a founding member of the Mass General Brigham healthcare system, reveals that statins may block a particular pathway involved in the development of cancer that results from chronic inflammation. The findings are published in Nature Communications.
“Chronic inflammation is a major cause of cancer worldwide,” said senior author Shawn Demehri, MD, PhD. “We investigated the mechanism by which environmental toxins drive the initiation of cancer-prone chronic inflammation in the skin and pancreas. Furthermore, we examined safe and effective therapies to block this pathway in order to suppress chronic inflammation and its cancer aftermath.”
Demehri and his colleagues’ study relied on cell lines, animal models, human tissue samples and epidemiological data. The group’s cell-based experiments demonstrated that environmental toxins (such as exposure to allergens and chemical irritants) activate two connected signaling pathways called the TLR3/4 and TBK1-IRF3 pathways. This activation leads to the production of the interleukin-33 (IL-33) protein, which stimulates inflammation in the skin and pancreas that can contribute to the development of cancer.
When they screened a library of U.S. Food and Drug Administration–approved drugs, the researchers found that a statin, pitavastatin, effectively suppresses IL-33 expression by blocking the activation of the TBK1-IRF3 signalling pathway. In mice, pitavastatin suppressed environmentally-induced inflammation in the skin and the pancreas and prevented the development of inflammation-related pancreatic cancers.
In human pancreas tissue samples, IL-33 was over-expressed in samples from patients with chronic pancreatitis and pancreatic cancer compared with normal pancreatic tissue. Also, in analyses of electronic health records data on more than 200 million people across North America and Europe, use of pitavastatin was linked to a significantly reduced risk of chronic pancreatitis and pancreatic cancer.
The findings demonstrate that blocking IL-33 production with pitavastatin may be a safe and effective preventive strategy to suppress chronic inflammation and the subsequent development of certain cancers.
“Next, we aim to further examine the impact of statins in preventing cancer development in chronic inflammation in liver and gastrointestinal tract and to identify other novel, therapeutic approaches to suppress cancer-prone chronic inflammation” said Demehri.
CRISPR-Cas9 is a customisable tool that lets scientists cut and insert small pieces of DNA at precise areas along a DNA strand. This lets scientists study our genes in a specific, targeted way.
Credit: Ernesto del Aguila III, National Human Genome Research Institute, NIH
A single infusion of a CRISPR-based gene-editing therapy significantly reduced low-density lipoprotein cholesterol (LDL-C, the ‘bad cholesterol’) in people who carry one gene for the inherited condition that results in very high LDL-C levels and a high risk of heart attack at an early age, according to findings presented at the American Heart Association’s Scientific Sessions 2023.
“Instead of daily pills or intermittent injections over decades to lower bad cholesterol, this study reveals the potential for a new treatment option – a single-course therapy that may lead to deep LDL-C lowering for decades,” said senior study author Andrew M. Bellinger, M.D., Ph.D., chief scientific officer at Verve Therapeutics in Boston.
The investigational treatment, VERVE-101, uses DNA-editing technology to permanently turn off the PCSK9 gene in the liver. PCSK9 is a gene that plays a critical role in controlling blood LDL-C through its regulation of the LDL receptor. People with heterozygous familial hypercholesterolaemia (ie, one gene for the disorder inherited from one parent) are treated with oral lipid-lowering medications such as statins as well as PCSK9 inhibitors to bring levels under control, though this only occurs in a small percentage of patients. The study presented is the first human trial of VERVE-101.
Earlier this year, the results of the researchers’ one-year animal study were published in Circulation. In that animal study, VERVE-101 lowered PSCK9 levels 67%-83% and LDL-C 49%-69%, depending on the dose. After a single dose, the reductions have now lasted 2.5 years, supporting the idea that VERVE-101 may potentially be an effective long-term or permanent treatment for high LDL-C.
The ongoing, first-in-human study included 7 men and 2 women in New Zealand or the United Kingdom: average age of 54 years; 8 white adults; and 1 Asian adult. Each participant was diagnosed with heterozygous familial hypercholesterolemia and had extremely high bad cholesterol levels (average measure of 201mg/dL) despite taking the maximum-tolerated LDL cholesterol-lowering medication.
“These numbers are consistent with the fact that, despite available treatments, only about 3% of patients living with heterozygous familial hypercholesterolemia globally have reached target treatment goals,” Bellinger said.
The majority of study participants had pre-existing severe coronary artery disease and had already experienced a heart attack, or undergone coronary bypass surgery or stenting to allow adequate blood flow to heart muscle. None were taking PCSK9 inhibitors while enrolled in the study.
Each participant received a single intravenous infusion of VERVE-101, with the first cohort (n=3) receiving a low dose of 0.1 mg/kg and other cohorts receiving escalating doses, after consultation with an independent safety monitoring board. The highest dose received was 0.6 mg/kg.
The study found that the highest-two VERVE-101 doses:
reduced LDL-C by 39% and 48% in the two participants receiving 0.45mg/kg of the drug and 55% in the sole participant receiving 0.6mg/kg;
reduced blood PCSK9 protein levels by 47%, 59% and 84% in the three participants receiving the 0.45 mg/kg or 0.6 mg/kg doses; and
reduced LDL-C at six months in the sole participant receiving 0.6mg/kg, with follow-up ongoing.
“We were thrilled to see that the previous testing we had done of VERVE-101 in animal models translated faithfully to these findings in humans,” Bellinger said.
Most adverse events encountered were mild and unrelated to treatment. Serious adverse cardiovascular events, specifically a cardiac arrest, a myocardial infarction and an arrhythmia, occurred in two patients who had underlying advanced coronary artery disease. “All safety events were reviewed with the independent data safety monitoring board, who recommended continuation of trial enrolment with no protocol changes required,” Bellinger said.
Studies involving a larger number of patients and with a control group will be required to fully document the efficacy and safety of VERVE-101, noted Bellinger.
The study is still enrolling patients to receive the highest-two doses of VERVE-101. After a year’s follow-up, each participant will go into a long-term follow-up study for an additional 14 years, as required by the FDA for all participants in any human genome editing trials.
Among the study’s limitations is that this is an interim report with a few participants who all received the treatment; therefore, no participants receiving an alternate treatment or no treatment were available for direct comparison. Results in the study were measured by reductions in LDL-C, not changes in the occurrence of heart attacks; however, LDL-C reduction is a well-known, validated endpoint among patients with heterozygous familial hypercholesterolaemia and coronary artery disease.
Colourised scanning electron micrograph of a breast cancer cell. Credit: NIH
A novel therapeutic approach that combines human epidermal growth receptor factor 2 (HER2)-targeted therapies with the cholesterol-lowering drug lovastatin can reduce the number of cancer treatments required to prevent tumour growth. Monitored by immuno-PET scans, this combination therapy has the potential to personalise treatment for cancer patients and spare them from harmful side effects. This research was published in The Journal of Nuclear Medicine.
Antibody-drug conjugates (ADCs) have become an eminent cancer treatment because of their ability to precisely target tumours with potent efficacy. HER2-ADC therapies have been effective in treating breast, lung, bladder, and stomach cancers. Although usually well-tolerated, multiple doses of the drugs can result in severe side effects, including low blood counts, liver damage, and lung damage. Strategies that reduce toxic side effects caused by ADCs and predictive biomarkers of ADC toxicity are currently an unmet clinical need.
“In this study, we sought to determine whether a single dose of HER2-ADCs could be administered in combination with lovastatin (which temporarily elevates cell-surface HER2) to achieve therapeutic efficacy similar to that of a multiple dose regime,” said Patricia Pereira, PhD, assistant professor at the Washington University School of Medicine. “We also used HER2-targeted immuno-PET to monitor changes in HER2 expression after ADC therapy.”
Researchers injected mice with cultured gastric cancer cells and patient-derived gastric cancer cells. When tumours grew sufficiently, the mice were divided into groups and received various treatment schedules (no treatment, multiple doses of ADC, multiple doses of ADC with lovastatin, single dose of ADC, or single dose of ADC with lovastatin). Immuno-PET was used to investigate the dosing regimen and the efficacy of the treatment schedules.
A single dose of ADC therapy combined with lovastatin was found to reduce tumour volume at rates similar to those resulting from multiple doses of ADC in a preclinical setting. The study results showed that immuno-PET can noninvasively monitor HER2 tumour levels after treatment with HER2-targeted ADC therapies.
“This preclinical work is significant because it has the potential to improve therapy for patients with HER2-positive cancers,” noted Pereira. “It not only simplifies treatment by exploring single-dose schedules of antibody-drug conjugates but can also reduce side effects by minimizing the number of doses required. Additionally, it personalises therapy using molecular imaging, enhancing treatment efficacy.”
She continued, “The findings suggest a future where molecular imaging techniques play a critical role in guiding drug development and cancer treatment decisions, particularly as various ADCs are being tested and approved for cancer treatment. Currently, there is no perfect way to select tumours or monitor their response to ADCs. This research indicates that molecular imaging can bridge this gap by providing real-time insights into therapy response.”
While high levels of low-density lipoprotein (LDL) can be reduced by drugs such as statins, reducing the risk of myocardial infarction and stroke, risk still remains in the form of other cholesterols. New research published in the journal Science describes how manipulating a protein involved in blood clot lysis could help bring cholesterol levels even more under control.
Heart disease remains a leading cause of death worldwide, despite advances in cholesterol-lowering medication such as proprotein convertase subtilisin-kexin type 9 inhibitors, which were approved by the FDA in 2015. One clinical trial following patients taking proprotein convertase subtilisin-kexin type 9 inhibitors demonstrated a benefit while also revealing an opportunity for improvement as the absolute risk reduction was considered modest at 1.5%.
“It is clear that there is more going on than just what statins and these newer inhibitor drugs can control,” says Ze Zheng, MBBS, PhD, MCW assistant professor of medicine. “More therapies are needed, and to get them we need to know more about other sources of risk for heart disease, especially heart attacks and strokes.”
So-called “bad cholesterol” is carried by apolipoprotein B (apoB) which forms well-structured particles with lipids and proteins. These particles serve as stable vehicles for transporting lipids such as cholesterol in the bloodstream. These lipid-rich particles mostly include very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL). Current cholesterol-lowering reduce mainly LDL levels, which though important to control, is not the only risk factor for heart disease. In fact, the other lipoproteins in the same group as LDL are not reduced by much with available treatments. Dr Zheng and her team are investigating how to reduce levels of other members of this family of lipoproteins, especially VLDL.
“With my background in lipid metabolism, I found myself consistently checking lipid levels even during studies regarding blood clot lysis and how an impairment in the body’s ability to remove blood clots affects the risk of blood vessel blockages,” Dr Zheng adds. “I was just naturally curious about it, and I noticed that a protein I was studying may have an effect on the amount of circulating cholesterol.”
In prior research, Dr Zheng has helped define a new cellular source of this protein, tissue-type plasminogen activator (tPA), and its role in breaking down blood clots and preventing blood vessel blockages. To understand its potential influence on cholesterol levels, her team used a gene-editing technique to stop liver cells from producing tPA in mice prone to blood vessel plaque formation. The scientists found that the mice developed increased lipoprotein-cholesterol in this experiment, and then validated the findings in follow-up studies using human liver cells and a type of rat liver cell known to produce VLDL in a way similar to human liver cells. With these and other experimental results, Dr Zheng and her team have demonstrated a new, important role that liver tPA influences blood cholesterol levels while underscoring a meaningful connection between the liver, heart and blood vessels.
“After defining this new role for tPA, we turned our attention to the question of how it changes blood cholesterol levels,” notes Wen Dai, MD, research scientist, Versiti Blood Research Institute.
The liver contributes to the majority of the “bad” apoB-lipoproteins by making VLDL. The team focused on whether and how tPA impacts the process of VLDL assembly in the liver. Microsomal triglyceride transfer protein (MTP) is required for the assembly of VLDL due to its role carrying lipids to the apoB. The scientists determined that tPA binds with the apoB protein in the same place as MTP. The more tPA is present, the fewer opportunities MTP has to connect with apoB and catalyse the creation of new VLDL. Essentially, MTP tries to pass a cholesterol to apoB, but tPA interferes with this pocess.
“Based on our prior research, we knew it also was critical to look at tPA’s primary inhibitor,” Dr. Zheng says.
Plasminogen activator inhibitor-1 (PAI-1) is known to block the activity of tPA. Scientists also have found a correlation between PAI-1 levels in blood and the development of disease due to plaque formation and blockages in blood vessels. The team found that higher levels of PAI-1 reduced the ability of tPA to bind with apoB proteins, rendering tPA less effective at competing with MTP to prevent VLDL production. Returning to the biological gridiron, PAI-1 might be a decoy receiver that distracts tPA until MTP connects with apoB for a big gain. The team studied this interaction in human subjects with a naturally occurring mutation in the gene carrying the code for PAI-1. The researchers found that these individuals, as predicted, had higher tPA levels and lower LDL and VLDL levels than individuals from the same community who did not have the same mutation.
“We are investigating therapeutic strategies based on these findings regarding tPA, MTP and PAI-1,” Dr Zheng notes. “I think we may be able to reduce the residual cardiovascular risk that has persisted even as treatment has advanced.”
New research published in eClinicalMedicine suggests that statins might protect patients with ulcerative colitis from developing and dying from colorectal cancer. The study, by Karolinska Insitut researchers, also found that statin treatment was associated with a lower risk of death regardless of cause in patients with ulcerative colitis or Crohn’s disease.
First author Jiangwei Sun notes that previous studies have shown that the risk of colorectal cancer in patients with IBD, such as ulcerative colitis and Crohn’s disease, is 50% higher than in the general population. This is likely to be because of the chronic gut inflammation that these patients have. Researchers have long sought drugs that can reduce the inflammation-related cancer risk.
“Even though more studies are needed to confirm our results, our study suggests that statins can prevent colorectal cancer in patients with inflammatory bowel disease (IBD), which is a high-risk group for this kind of cancer,” says Dr Sun.
The observational study conducted by Dr Sun and his colleagues compared over 10 500 IBD patients from around the country, of whom half were statin users; the other half of the group, who were matched with the first, were not. After a follow-up period of, on average, 5.6 years, 70 of the statin group and 90 of the non-statin group had been diagnosed with colorectal cancer.
The effect increased over time
The protective effect was directly proportional to the length of time the patient had been on statins and could be demonstrated after two years’ treatment.
There were also fewer deaths from colorectal cancer in the statin group (20) than in the non-statin group (37) during the study period, and deaths regardless of cause (529 versus 719).
The study shows that some 200 IBD patients need to be treated with statins to avoid one case of colorectal cancer or death from the cancer within ten years of treatment onset. The protective effect was only statistically valid for patients with ulcerative colitis.
“We think this is because the study contained fewer patients with Crohn’s disease,” explains Dr Sun. “More and larger studies compiling data from patient populations in many countries will probably be needed to achieve statistical significance for Crohn’s disease.”
Significantly fewer deaths
To avoid death regardless of cause during the same ten-year period, the number of treated patients dropped to 20, on account of how statins also protect against more common conditions, such as cardiovascular disease. Statins were linked to fewer deaths in both ulcerative colitis and Crohn’s disease patients.
The study was based on the ESPRESSO-cohort, which is run by its initiative-taker Jonas F Ludvigsson, paediatrician at Örebro University Hospital and professor at Karolinska Institutet, and the study’s last author.
“In that we can combine tissue data from patients with colorectal cancer with data from Swedish health registries, we’re uniquely placed to study the long-term effects of drugs for IBD,” he says. “Our hope is that these studies will improve the care of IBD patients.”
The most solid evidence so far
According to the researchers, the new results provide the most solid evidence so far that statins could be an effective prophylactic for colorectal cancer among people with IBD. However, more knowledge must be gathered before the treatment can be recommended in general guidelines.
“More studies are needed to ascertain if there is a causal relationship, at what point of the pathological process statins should be administered, what a reasonable dose would be and how long treatment needs to last if it’s to be of benefit,” says Dr Sun.
Patients who have had an intracerebral haemorrhage who take cholesterol-lowering drugs called statins may have a lower risk of having another stroke, especially ischaemic stroke, compared to people who also had an intracerebral haemorrhage but were not taking statins, according to a new study published in Neurology, the medical journal of the American Academy of Neurology.
“Previous research has had mixed results on the risk of stroke in people who are taking statins and have already had a bleeding stroke, so we evaluated this further,” said study author David Gaist, MD, PhD, of the University of Southern Denmark in Odense and a member of the American Academy of Neurology. “We looked at whether use of statins after a bleeding stroke is associated with the risk of any additional stroke, including both those caused by bleeding and by blood clots. We found that those who used statins had a lower risk of stroke, notably ischaemic stroke, while there was no change in the risk of bleeding stroke.”
For the study, researchers looked at health records in Denmark and identified 15 151 people who had a first bleeding stroke.
People were followed from 30 days after their first bleeding stroke until the first occurrence of another stroke, death, or the end of follow-up, which on average lasted 3.3 years. Researchers used prescription data to determine information on statin use.
Researchers then compared 1959 people who had another stroke to 7400 people who did not have another stroke who were similar in age, sex and other factors. Of those who had another stroke, 757 people, or 39%, took statins compared to 3044 people, or 41%, of those who did not have a second stroke.
After adjusting for factors like hypertension, diabetes and alcohol use, statin use was associated with a 12% lower risk of another stroke.
Then they compared 1073 people who had an ischaemic stroke to 4,035 people who did not have another stroke. Of those who had an ischaemic stroke, 427 people, or 40%, took statins compared to 1687 people, or 42%, of those who did not have another stroke.
After adjusting for similar factors, statin use was associated with a 21% lower risk of an ischaemic stroke after the initial bleeding stroke.
They also compared 984 people who had another bleeding stroke to 3755 people who did not have another stroke. Of those who had a recurrent bleeding stroke, 385 people, or 39%, took statins compared to 1532 people, or 41%, of those who did not have another stroke.
After adjustments, researchers did not find a link between statin use and recurrent bleeding stroke.
“The results of our study are good news for people taking statins who have had a bleeding stroke,” Gaist added. “While we did find a lower risk of having another stroke, it is important to note that when looking at the data more closely, that lower risk was for ischaemic stroke. Still, we found no increased risk for bleeding stroke. More studies are needed to confirm our findings.”
A limitation of the study was that it only included the Danish population, which is primarily people of European ancestry, and may not be generalisable to people from other populations.
A new study published in the New England Journal of Medicine found that statins, a class of cholesterol-lowering medications, may offset the high risk of cardiovascular disease in people living with HIV by more than a third, potentially preventing one in five major cardiovascular events or premature deaths in this population. People living with HIV can have a 50–100% increased risk for cardiovascular disease.
“This research suggests that statins may provide an accessible, cost-effective measure to improve the cardiovascular health and quality of life for people living with HIV,” said Gary H. Gibbons, MD, director of the National Heart, Lung, and Blood Institute (NHLBI), a study funder. “Additional research can further expand on this effect, while providing a roadmap to rapidly translate research findings into clinical practice.”
For the double-blinded phase 3 trial, known as Randomised Trial to Prevent Vascular Events in HIV (REPRIEVE) study, researchers randomised participants into either a treatment group, where they received pitavastatin calcium daily or a control group receiving placebo. The researchers followed participants for about five years, but ended the trial early when they discovered the treatment benefits outweighed potential risks.
To understand the benefits, the researchers compared how often participants in each group experienced major cardiovascular events, including heart attacks, strokes, or surgery to open a blocked artery. They found participants who took daily pitavastatin had 35% fewer major cardiovascular events than those who took a placebo. The researchers also measured the number of deaths in combination with major cardiovascular events during the study period and found participants in the treatment group were 21% less likely than those in the placebo group to experience these events. Additionally, those taking pitavastatin had a 30% reduction in their low-density lipoprotein (LDL) cholesterol levels.
“Lowering LDL cholesterol levels reduces risks for cardiovascular events, like having a heart attack and stroke, but these findings suggest there may be additional effects of statin therapy that explain these reduced risks among people living with HIV,” said Steven K. Grinspoon, MD, the study chair. “Ongoing research about how statin therapy may affect inflammation and increased immune activation among people with HIV may help us better understand the additional benefits we’re seeing with this treatment approach.”
To support optimal health outcomes among the study participants, normal liver and kidney function were an enrolment criteria. They were also required to take antiretroviral therapy, which itself is critical to reducing the risk of HIV complications and related comorbidities, including cardiovascular disease.
Beginning in 2015, REPRIEVE enrolled 7769 adults, ages 40–75, from 145 sites in 12 countries. Adults in the study were an average age of 50 and had low-to-moderate risks for cardiovascular disease, which meant they normally would not have been prescribed statins. Women accounted for 31% of participants. Approximately 41% of study participants identified as Black, 35% as white, 15% as Asian, and 9% as another race.
Using new genetic tools to study statins in human cells and mice, researchers have uncovered how these drugs protect the cells that line blood vessels. Published in Nature Cardiovascular Research, the findings provide new insight into statins’ curiously wide-ranging benefits, for conditions ranging from arteriosclerosis to diabetes, that have long been observed in the clinic.
“The study gives us an understanding, at a very deep mechanistic level, of why statins have such a positive effect outside of reducing LDL [low-density lipoprotein],” said professor of medicine Joseph Wu, MD, PhD, the study’s senior author. “Given how many people take statins, I think the implications are pretty profound.”
Developed in the 1980s from compounds found in mould and fungi, statins target an enzyme that regulates cholesterol production in the liver. But clinical trials have shown that they also seem to safeguard against cardiovascular disease beyond their ability to lower cholesterol.
Heart failure patients who take statins, for example, are less likely to suffer a second heart attack. They have also been shown to prevent the clogging of arteries, reduce inflammation and even lower cancer risk. Yet these underlying mechanisms are poorly understood.
“Statins were invented to lower cholesterol by targeting the liver. But we didn’t know the targets or the pathways in the cardiovascular system,” said Chun Liu, PhD, an instructor at the Stanford Cardiovascular Institute and co-lead author.
Mesenchymal cells are poor substitutes
To take a closer look at statins’ effect on blood vessels, Liu and colleagues tested a common statin, simvastatin, on lab-grown human endothelial cells derived from induced pluripotent stem cells. Endothelial cells make up the lining of blood vessels, but in many diseases they transform into a different cell type, known as mesenchymal cells, which are poor substitutes.
“Mesenchymal cells are less functional and make tissues stiffer so they cannot relax or contract correctly,” Liu said.
The researchers suspected that statins could reduce this harmful transition. Indeed, endothelial cells treated with simvastatin in a dish formed more capillary-like tubes, a sign of their enhanced ability to grow into new blood vessels.
RNA sequencing of the treated cells offered few clues. The researchers saw some changes in gene expression, but they “didn’t find anything interesting,” Liu said.
It was not until they employed a newer technique called ATAC-seq that the role of statins became apparent. ATAC-seq reveals what happens at the epigenetic level, meaning the changes to gene expression that do not involve changes to the genetic sequence.
They found that the changes in gene expression stemmed from the way strings of DNA are packaged inside the cell nucleus. DNA exists in our cells not as loose strands but as a series of tight spools around proteins, together known as chromatin. Whether particular DNA sequences are exposed or hidden in these spools determines how much they are expressed.
“When we adopted the ATAC-seq technology, we were quite surprised to find a really robust epigenetic change of the chromatin,” Liu said.
ATAC-seq revealed that simvastatin-treated cells had closed chromatin structures that reduced the expression of genes that cause the endothelial-to-mesenchymal transition. Working backward, the researchers found that simvastatin prevents a protein known as YAP from entering the nucleus and opening chromatin.
The YAP protein is known to play important roles in development, such as regulating the size of our organs, but also has been implicated in the abnormal cell growth seen in cancer.
A look at diabetes
To see the drug in context, the researchers tested simvastatin on diabetic mice. Diabetes causes subtle changes to blood vessels that mimic the damage commonly seen in people who are prescribed statins — older patients who do not have a cardiovascular condition, Liu said.
They found that after eight weeks on simvastatin, the diabetic mice had significantly improved vascular function, with arteries that more easily relaxed and contracted.
“If we can understand the mechanism, we can fine-tune this drug to be more specific to rescuing vascular function,” Liu said.
The findings also provide a more detailed picture of the vascular disease process, which could help doctors identify and treat early signs of vascular damage.
